Acquired immunodeficiency syndrome, caused by human immunodeficiency virus-1 (HIV-1) infection, is the most common cause of dementia in non-aged individuals in the US. Highly active, or combined, antiretroviral therapy (HAART or cART) has controlled viral replication and immunosuppression, and initially reduced the severity of neurologic disease. However, with increased patient lifespan the prevalence of more moderate cognitive and motor disease has increased. Most AIDS patients now develop neurologic and/or psychiatric symptoms during their disease course, and pathology is seen in most brains at autopsy. There is also an increasing incidence of dementia in patients receiving HAART, attributed to emergence of neurovirulent strains, to viral resistance, or to long-term CNS exposure to toxic, therapeutics. HIV neuropathology thus remains a serious clinical problem. What is the basis of HIV neurologic deficits? HIV proteins such as gp120, Tat, Vpr and Nef are directly neurotoxic, and may also modulate indirect toxicity by causing functional changes in astroglia and microglia (ex: chemo/cytokine secretion, [Ca2+]i destabilization). Damage to myelin or oligodendrocytes (OLs), would enhance neurologic dysfunction. "Myelin pallor" is an anomaly consistently reported in HIV patients. It was historically attributed to vasculitis and subsequent blood brain barrier leakage. Even if vasculitis is involved in myelin pallor, OLs/myelin may also be more immediate targets of viral proteins, since white matter defects are observed when myelin pallor is absent. Our central hypothesis is that chronic exposure to HIV proteins causes direct damage to OLs and/or myelin. To support the hypothesis, we showed that even short periods of Tat induction in a transgenic mouse caused caspase-3 expression, and abnormal morphology and ultrastructure in OLs. The findings after acute exposure suggest that chronic exposures typical in HIV patients may further damage OLs and myelin and contribute to neurologic dysfunction. This R21 proposal contains in vivo studies that assess the extent and character of white matter and OL/myelin damage after chronic exposure (6 months) to HIV-1 Tat. Aim 1 tests the hypothesis that chronic exposure causes escalating damage to OLs and myelin, using biochemical, stereological, and ultrastructural methods. The effect of gender is examined as a critical variable. Aim 2 uses in vitro methods to test the hypothesis that OLs are direct targets of Tat and of HIV. Studies address potential mechanisms that may lead to interventions. All results are correlated with MRI studies of chronic exposure that are already underway. PUBLIC HEALTH RELEVANCE: HIV infection causes central nervous system dysfunction, even in patients receiving anti-retroviral therapy. With longer patient lifespans, the prevalence of neurologic dysfunction in HIV has increased in recent years. White matter abnormalities, assessed by imaging or histology, are reported in many HIV patients. White matter defects may contribute to symptoms, and may also represent a therapeutic target. This project uses a chronic in vivo model of HIV protein exposure to systematically describe components of white matter damage in males and females. Culture studies with viral protein and HIV test whether oligodendrocytes are directly affected.